Assessing the impact of contraceptive use on mental health among women of reproductive age – a systematic review

Background Contraceptive use is the principal method by which women avoid unintended pregnancy. An unintended pregnancy can induce long-term distress related to the medical, emotional, and social consequences of carrying that pregnancy to term. Objectives This review investigates the effects of modern contraception techniques such as birth control pills, long-acting reversible contraceptives (e.g., intrauterine devices, implants), and condoms on mental health status. Methods We searched multiple databases from inception until February 2022, with no geographical boundaries. RCTs underwent a quality assessment using the GRADE approach while the quality of observational studies was assessed using the Downs and Black scoring system. Data were analyzed through meta-analysis and relative risk and mean difference were calculated and forest plots were created for each outcome when two or more data points were eligible for analysis. Main results The total number of included studies was 43. In women without previous mental disorders, both RCTs (3 studies, SMD 0.18, 95% CI [0.02, 0.34], high quality of evidence) and cohort studies (RR 1.04 95% CI [1.03, 1.04]) detected a slight increase in the risk of depression development. In women with previous mental disorders, both RCTs (9 studies, SMD − 0.15, 95% CI [-0.30, -0.00], high quality of evidence) and cohort studies (SMD − 0.26, 95% CI [-0.37, -0.15]) detected slight protective effects of depression development. It was also noticed that HC demonstrated protective effects for anxiety in both groups (SMD − 0.20, 95% CI [-0.40, -0.01]). Conclusions Among women with pre-existing mental disorders who use hormonal contraceptives, we reported protective association with decreased depressive symptoms. However, the study also draws attention to some potential negative effects, including an increase in the risk of depression and antidepressant use among contraceptive users, a risk that is higher among women who use the hormonal IUD, implant, or patch/ring methods. Providers should select contraceptive methods taking individual aspects into account to maximize benefits and minimize risks. Supplementary Information The online version contains supplementary material available at 10.1186/s12884-024-06587-9.


Akhondzadeh 2003
Iran Private RCT 32 Investigate the efficacy of ethinyl estradiol as an adjuvant agent in the treatment of premenopausal women with chronic shizophrenia Inpatients in the active phase of illness, meet the DSM-IV criteria for chronic schizophrenia Positive and negative symptoms as measured on the PANSS and the (extrapyramidal symptoms rating scale) ESRS Patients were randomly allocated to receive haloperidol 15 mg/day plus ethinyl estradiol 0.5 mg/day or haloperidol 15 mg/day plus placebo

weeks Positive Symptoms
The difference between the two protocols was significant as indicated by the effect of group, the between-subjects factor (Greenhouse -Geisser corrected: F = 6.17, df = 1, P=.019).

Negative Symptoms
The difference between the two protocols was not significant as indicated by the effect of group, the between-subjects factor (Greenhouse -Geisser corrected: F = 0.088, df = 1, P=.76).
Patients who received the ethinyl estradiol showed better clinical outcomes with respect to positive symptoms, general psychopathological symptoms, and PANSS total scores Bengtsdotter 2018 Sweden University hospitals RCT 202 To assess whether women with ongoing or previous mental health disorders or risk use of alcohol at baseline are at higher risk for COC-induced mood symptoms.
Healthy women (18-35 years) with a body mass index between 17 and 30 kg/m2 who accepted to use back-up contraception.Ongoing or previous mental disorders and present use of psychotropic drugs were not reason for exclusion.
Primary outcome-change scores in daily, prospective symptom ratings of 5 mood symptoms on the DSRP scale.
The presence of ongoing primary depressive and anxiety disorders as well as eating disorders was established by use of the Swedish 6.0.0 version of the Mini International Neuropsychiatric Interview COC (1.5 mg estradiol and 2.5 mg nomegestrolacetate) or placebo during three 24/4 treatment cycles 84 days Women with ongoing or previous mood, anxiety or eating disorders allocated to COC had higher total DRSP D-scores during the intermenstrual phase of the treatment cycle in comparison with corresponding women randomised to placebo, mean difference 1.3 (95% CI 0.3-2.3).In contrast, among women without mental health problems, no difference in total DRSP D-scores between COC-and placebo users was noted.Women with a risk use of alcohol who were randomised to the COC had higher total DRSP D-scores than women randomised to placebo, mean difference 2.1 (CI 95% Eligible participants were between 18 and 75 years and were not on antidepressants, antipsychotics, and/or mood stabilizers for at least 7 days before randomization.
Responders were defined as patients with a 50% or greater reduction in their baseline PSS score on days 7 and 56.Patients with less than a 50% reduction from baseline at either day 7 or 56 were defined as nonresponders.
Patients requiring rescue treatment with antipsychotic or mood stabilizer medications were also defined as nonresponders.
Patients were randomly assigned 1:1:1:1 to receive either active treatment of mifepristone at 1 of 3 dose levels (300 mg, n =107; 600 mg, n = 107; 1200 mg, n = 109) or placebo (n = 110) 56 days Mifepristone was well tolerated at all 3 doses.The proportion of responders randomized to mifepristone did not statistically differ from placebo.Patients with trough mifepristone plasma concentrations greater than 1660 ng/mL were significantly more likely to have a rapid and sustained reduction in psychotic symptoms than those who received placebo.The study failed to demonstrate efficacy on its primary end point.However, the replication of a statistically significant linear association between mifepristone plasma concentration and clinical response indicates that mifepristone at sufficient plasma levels may potentially be effective in rapidly and durably reducing the psychotic symptoms of patients with psychotic depression.Participants randomized to the treatment group either received 100 or 200 µg oestradiol (administered as transdermal patches).Placebo patches were adhesive and identical in appearance but had no active substance.Patches were changed every 3.5 days.

weeks
The MADRS depression scores comparing oestrogen 200 mcg to placebo fluctuated between borderline significance (p = 0.05) at day 7, to non-significant at day 14 (p = 0.07) to significant at day 28 and back to borderline significance at day 56.There were no significant differences found comparing oestrogen 100 mcg with oestrogen 200 mcg or oestrogen 100 mcg with placebo at other time points.
Authors concluded adjunctive oestradiol treatment for depression may be a promising treatment for women with comorbid depression and schizophrenia.Women aged 18-35 with a body mass index below 30 kg/m2 who accepted use of back-up contraception during the study period.
The primary outcome was the Daily Record ofSeverity of Problems (DRSP), which was filled out daily during one baseline cycle and the final treatmentcycle.
Participants were randomized to 1.5 mg estradiol and 2.5 mg nonmegestrolacetate or placebo during three 24/4 treatent cycles (24 days of treatment, followed by 4 pill-free days).
Authors concluded COC use is associated with small but statistically significant mood side effects in the inter-menstrual phase.However, positive mood effects are noted in the premenstrual phase and the proportion of women with clinically relevant mood worsening did not differ between treatment groups.Women with moderate to severe premenstrual symptoms The primary outcome measure consisted of the 21 symptom items of the DRSP, which are rated on a six-point scale from 1 (not at all) to 6 (extreme).Secondary outcome measures included the three functional impairment items of the DRSP and the Premenstrual Tension Scales observer-rated (PMTS-O) and selfrated (PMTS-SR) scales.
The OC formulation (Drospirenone 3 mg and ethinyl estradiol 20 ug) or placebo was administered for 24 days in a 28-day cycle (24/4) for three cycles and then after a washout period of one treatment-free cycle switched to the alternate treatment.

cycles
Women who began with the D/EE treatment initially, reported a 51% improvement in mood compared to 31% in the placebo group.After cross over, mood improved 34% for the D/EE group, and women who were switched to the placebo saw a 17% worsening of their mood.
This was a cross over study design -so people were randomized to either begin with placebo or intervention group, then after a 3 week washout period, were switched to the other intervention.

Women with symptoms of premenstrual dysphoric disorder
The difference between the average luteal phase Daily Record of Severity of Problems total scores from the 2 qualification cycles and the average luteal phase Daily Record of Severity of Problems total scores from the 3 treatment cycles.
An OCP formulation containing drospirenone 3 mg and ethinyl estradiol 20 ug.Hormones were administered for 24 days, followed by 4 days of inactive pills (24/4) for 3 cycles.

cycles
The  2 complete menstrual cycles There were no significant differences between the three groups in cyclic changes for any physical rating, but there were for tiredness or fatigue (non-OC users reported experiencing tiredness or fatigue more frequentiy than the OC users) and sadness or depression (non-OC users experienced sadness or depression less frequently than OC users during the early part of the cycle, followed by a sharp rise from early premenstrual to the menstrual phase).There were no significant cyclic differences in ratings between the monophasic and triphasic groups.
Beral Oral contraceptive pills 20 years of follow-up Non-users of oral contraception were used as the reference category.
The odds of a non-user experiencing depressive symptoms were 1.43 (95% CI = 1.28-1.58)times that of an OCP user.After adjustment for confounders, women who used OCP for reasons other than contraception were 1.32 (95% CI = 1.07-1.62)times as likely to report depressive symptoms as women who used OCP for contraception.
Nonsignificant results when adjusted for factors known to be associated with depression.Previously mentally healthy HC users had an OR of 1.79 for use of antidepressants compared with nonusers, whereas this number was 1.28 for women with previous mental health issues.The highest antidepressant use were uniformly found in strata with previous mental health issues, with highest usage in women aged 24-30 with no immigrant background, low income and HC use (51.4%).The largest difference in antidepressant use between HC users and non-users was found in teenagers, and in adult women of immigrant background with low income.Of the total individual variance in the latent propensity of using antidepressant 9.01% (healthy) and 8.16% (with previous mental health issues) was found at the intersectional stratum level

Reporting External validity
Total score

Table S1 :
Characteristics of Randomized Controlled Trials from baseline to late luteal phase was significantly greater with LNG/EE than placebo at the late luteal phase of the first estimated cycle (−30.52±1.73[SE] vs. −22.47±1.77;p<.001)and the worst 5 days during the last ontherapy estimated cycle(−26.77±1.83 vs. −20.89±1.82;p=.016).Women aged 18-45 with regular 26-35 day menstrual cycles predictable within 7 days, no hormonal contraceptive use within the past 6 months, onset of depressive disorder at least 3 months prior to study participation, use of current antidepressant for at least 3 months, depressive disorder in full remission for at least 2 months with exception of premenstrual week, and willingness to use barrier contraceptive methods.The primary outcome was the percent change in the mean premenstrual Montgomary-Asberg Depression Rating Scale (MADRS) score from baseline (Average of last 5 days prior to mense during the run-in period) to the second treatment month (obtained on days 25-28 of the OCP cycle and reflecting the week prior to the withdrawal bleed).21days of EE 30 µg/day plus DRSP 3 mg/day with double-blinded assignment to daily EE 30 µg (EE/DRSP+EE) or placebo (EE/DRSP+placebo) during the final 7 days of each 28-day cycle.3monthsPrementstrualMADRS(p=0.0019) and Daily Rating of Severity of Problems scores (p=0.0001)improvedsignificantly in both groups and did not differ between the treatment and placebo groups.Authors concluded that the addition of EE/DRSP (+/-EE) to antidepressants may treat premenstrual breakthrough of depression.Women aged 14-45 with schizophrenia and ongoing symptoms of psychosis Positive and Negative Syndrome Scale (PANSS) score > 60 despite a stable dose of antipsychotic medicationThe primary outcome was the Positive and Negative Syndrome Scale (PANSS) score, as well as the Montgomery Asberg Depression Scale (MADRS) score.
days of OCP use indeed reduced prefrontal cortical thickness, with the most pronounced effect in the right inferior frontal gyrus; OCPs also produced negative mood symptoms as self-reported on the BDI and DRSP.Oral contraceptives significantly increased total score of self reported symptoms on the DRSP.

Table S3 :
Setting of the included studies

Table S4 :
Quality Assessment of the Observational Studies